This proposal is designed to enrich Andrew T. Chan, MD's career development in cancer prevention epidemiology through an integration of mentored research experience with formal coursework at the Harvard School of Public Health. The proposed research aims to improve prevention of colorectal cancer using the resources of three large, prospectively followed cohorts -- the Nurses'Health Study (NHS), the Health Professionals Follow-up Study (HPFS), and the Adenoma Prevention with Celecoxib (APC) Trial. The analyses will focus on three promising areas of prevention which complement existing efforts in screening and removal of adenomas, the precursor lesions for the vast majority of colorectal cancer. First, the research plan seeks to clarify the role of aspirin, non-steroidal anti-inflammatory drugs, and cyclooxygenase-2 selective inhibitors in chemoprevention. In particular, the analyses will provide urgently needed data on the optimal dose and duration of use of such agents for the prevention of initial adenoma in an average risk population. Moreover, the role of genetic variation in metabolism of these drugs in modulating their potential benefit will be investigated. Second, the proposal will examine modifiable risk factors, which are common to coronary heart disease (CHD) and colorectal adenoma and investigate the application of current CHD biomarkers in the prediction of colorectal neoplasia. Finally, the planned research aims to clarify the role of hyperplastic polyps in risk stratification for subsequent adenoma. To pursue these aims, Dr. Chan will design prospective studies using multivariable models. The overarching methodological strength is the inclusion of three large cohorts with complementary features: the NHS and HPFS allow analysis of initial colorectal adenoma, with extended follow-up and repeated exposure measures;the APC trial permits analysis of recurrent adenoma, with uniform surveillance of subjects. This research plan will provide important information on adenoma prevention and risk assessment for improved population-based surveillance and screening. Moreover, Dr. Chan will obtain experience in several study designs -- including observational cohort, case-control, and clinical trials -- and data ranging from questionnaires, biomarkers, and genetic polymorphisms. This overall proposal will ensure that Dr. Chan will become an established independent investigator and a leader in cancer prevention.